The present invention relates to agents for use in the prevention and treatment of iron overload disease states. More specifically, the present invention relates to a class of porphyrins and metalloporphyrins that inhibit heme iron uptake.
Iron overload syndromes are a significant cause of morbidity and mortality throughout the world. In the United States alone, about one in every 250 suffers from one such disease, hemochromatosis, which is a hereditary disease characterized by overabsorption of iron by the intestine. Iron overload is also associated with other diseases including, but not limited to, thalassemia and sickle cell anemia. In part, the iron overload often associated with sickle cell anemia and thalassemia may be attributed to iron acquired from frequent blood transfusions. Patients found to be afflicted with such disorders are often faced with a daunting prescription of treatments with unpleasant side effects and a food supply widely fortified with iron which may serve to counter the good done by any remedy used. In the developed world, two thirds of the iron that is absorbed by a patient is generally derived from heme (or “organic iron”), often present in foods such as red meats, rather than from inorganic iron. In some individual cases of iron overload disease, the disease may also in part be attributed to a high dietary intake of iron.
Iron overload disorders are often difficult to diagnose. This difficulty often arises from the fact that the symptoms presented by many such disorders are often vague and shared with a host of other common diseases. Some of these symptoms include joint pain, fatigue, and abdominal pain. In addition, since it was long believed that iron overload disorders were rare, alternative diagnoses were often favored by physicians. When such a disorder is suspected, however, relatively simple blood tests such as a transferrin saturation test may be performed to measure levels of blood iron and ferritin (a protein indicative of levels of iron stores in the body), and thus confirm or reject the diagnosis. In some cases, patients may be counseled to undergo further testing, possibly including a liver biopsy and/or genetic testing to assure the diagnosis.
Overload of iron in the body leads to deposition of iron in tissues, eventually damaging them if allowed to progress. Joints may be subject to damage, as well as organs such as the pancreas, liver, and heart. When diseases characterized by iron overload go undiagnosed, medical problems including heart disease, arthritis, diabetes, and liver cancer may result.
Once diagnosed, traditional methods of treatment of many iron overload disorders call for the creation and maintenance of a mild anemia in a patient to draw stored iron out of body tissues by incorporating it into new red blood cells. Iron is normally eliminated from the body in minute amounts by the shedding of skin, and by loss of blood. Thus, many traditional methods of treating iron overload syndromes call for the physical removal of iron from the system of a patient using systematically-repeated phlebotomy. Following phlebotomy, stored iron is mobilized for incorporation into new hemoglobin produced in new red blood cells formed to replace those removed with the patient's blood. The patient's blood is monitored throughout the course of treatment to evaluate the levels of iron present in the patient's body and the level of anemia induced by the treatment. Repeated withdrawal of blood eventually depletes the patient's excess stores of iron. Once this has been accomplished, the frequency of phlebotomy may be greatly reduced, with many patients requiring only 2–6 phlebotomies per year following the initial de-ironing process. The initial de-ironing stage may last from less than six months to several years, however.
Such regimens of phlebotomy are generally not an option in patients already exhibiting anemia, however. Similarly, in some patients having iron overload-induced cardiac failure, blood loss such as that caused by phlebotomy can present a significant problem. Further, in individuals with iron-overload due to ineffective erythropoesis or transfusion dependence, removal of iron by phlebotomy may often prove problematic since the individuals are already critically anemic. As a result, therapies involving phlebotomy are not suitable for use with all patients.
An alternative therapy for reducing organic iron stores has become available for use with some such patients for whom phlebotomy would be unsuitable. In this alternative therapy, a patient is administered a chemical chelating agent known as deferoxamine. Deferoxamine binds with iron in the bloodstream, producing a complex that is then removed from the bloodstream by the kidneys and excreted from the patient's body with urine. In some instances, deferoxamine is administered to a patient as a subcutaneous injection, in others, as a continuous infusion delivered by an infusion pump. Deferoxamine has known side effects, however, and may be damaging to individuals with kidney disease. In addition, for some individuals, the anemia induced by deferoxamine treatments may be severe enough to prevent further phlebotomy, while still failing to effectively remove the excess iron from the patient's body.
Deferoxamine is currently the only available drug treatment for iron-overload syndromes. Deferoxamine is limited in its efficacy by its poor oral absorption. It is also rapidly metabolized in the plasma. As a result of this, deferoxamine is generally administered to a patient by continuous subcutaneous infusion. Adverse effects of deferoxamine treatment may include skin discoloration, ocular and auditory abnormalities, sensor motor neurotoxicity, altered renal function, difficulty breathing, muscle cramping, and pulmonary toxicity. In addition, growth retardation has been observed in some children on long-term deferoxamine treatment. These side effects may be ameliorated by the use of slow continuous infusion administration methods. Unfortunately, however, patient compliance with slow continuous infusion regimes is often a problem.
In addition to the inconvenience and side effects, deferoxamine treatment is only partially effective in treating iron overload syndromes. More specifically, while deferoxamine appears able to slowly decrease iron stores in iron-overloaded individuals, it does not act to prevent continued intake of iron from the intestine. This may allow continual replenishment of the iron stores, countering the benefits of the treatments, and thus increasing their length.
It is thus observed that there is a clear need in medicine for more effective therapies and therapeutic agents for use in treating medical conditions associated with iron overload. Since in most cases the iron ingested is present in a patient's body in an accessible form as heme-iron, an inorganic iron-chelating agent is useful to actively reduce iron stores in a patient's body. The utility of such compounds is lessened, however, by the inability to prevent replenishment of bodily stores of iron. Indeed, there are to date no means available for decreasing the absorption of heme by a patient except for strict dietary restrictions, including absolute avoidance of all meat and of plant products containing heme. Such restrictions are often difficult for patients to implement and adhere to since even plant-based foodstuffs often contain cytochromes—proteins often containing heme. It would thus be beneficial to provide a composition for inhibiting heme iron absorption by a patient. Such compositions could render phlebotomy or chelating therapies more effective. In addition, such compositions could potentially serve to help patients afflicted with iron overload maintain healthy levels of iron after initial de-ironing is completed using more traditional therapies.
In some circumstances, a heme iron uptake inhibitor could be used to increase the effectiveness of known or currently unknown chelation therapies by reducing the input of new iron into the system of a patient. This could be implemented while currently known therapies such as monitored phlebotomy or the administration of deferoxamine or other chelating agents are used to remove the currently existing iron stores. Further, a heme-iron uptake inhibitor could potentially be used concurrently with or at the initiation of a transfusion program for sickle cell anemia, thalassemia, or another disorder requiring frequent transfusions of blood in order to limit the patient's iron acquisition to that of the transfusion. Such an inhibitor may also be useful as a preventative agent to reduce the intake of iron and reduce the iron burden in the diseases outlined above. Such agents would thus be beneficial for the use of a previously-de-ironed patient seeking to avoid subsequent re-accumulation of iron. Finally, such an inhibitor may be useful in the treatment of other conditions in which high levels of iron may be harmful, including severe cardiac disease or hemochromatosis heterozygotes in which mild iron excess has been demonstrated to lead to coronary artery disease.